Acute kidney injury (AKI) is among the leading cause of morbidity and mortality of hospitalized patients, and novel treatment options are urgently needed. The main goal of this proposal is to identify the functional contributions of adenosine transporters to renal protection from AKI. Moreover, we will utilize our findings in AKI to better understand the hypoxic adenosine response in acute or chronic states of lung injury and sickle cell disease (SCD). As such, our findings will address functional differences of extracellular adenosine during disease progression from acute injury into chronic disease states. Adenosine signaling plays an important role in tissue adaptation during hypoxia. Adenosine's effects are terminated via uptake from the extracellular towards the intracellular compartment through equilibrative nucleoside transporters (ENTs). Studies from our laboratory show that inhibition of ENTs enhances adenosine signaling during hypoxia and promotes protection from AKI. Studies in mice with genetic deletion of Enti or Ent2 identified a selective phenotype in Entl'^' mice, including higher adenosine levels, preserved kidney function, and attenuated inflammation. Subsequent studies of ENT inhibitor treatment in mice with deletion of individual adenosine receptors suggested the AD0RA2B adenosine receptor mediates kidney protection from AKI. Therefore, we hypothesize that inhibition or deletion of ENTI promotes kidney protection from ischemia by increasing extracellular adenosine and signaling events through the AD0RA2B. Four specific aims are proposed: Aim 1: Define the cell-specific contributions of ENTs during AKI, Aim 2: Study the transcriptional control of ENTs during ischemic AKI, Aim 3: Study the cell-specific functions of adenosine receptors in ENT-dependent kidney protection during ischemic AKI, and Aim 4: Study the role of the hypoxic adenosine response in AKI- driven lung injury. Together, these studies will provide novel insight into how the hypoxic adenosine response varies among different organ systems, which will help guide the use of adenosine-based therapeutics for kidney, lung and SCD associated disorders. RELEVANCE (See instructions): Acute injury to the kidney and the lung are common and devastating. We know little about the basic mechanisms of tissue protection in these disorders. The work proposed in this application will seek to define novel drug targets for the treatment of acute injuries that could provide significant advancements to public health.